PROJECT SUMMARY Telomere length and telomerase activity have been posited as biomarkers for cellular aging, longevity, and age-related conditions such as cardiovascular disease and type 2 diabetes. Their role in the pathophysiology of chronic diseases, however, is still not well-defined, as they have been shown to also be influenced by adiposity. Moreover, information on the role of genetics in telomere biology is scarce. The objectives of the proposed study are to explore the phenotypic and genotypic relationship between body composition measures (e.g., obesity) and telomere length and telomerase activity, and to investigate the role of telomere length and telomerase activity on metabolic risk factors and disease in adults. Using a longitudinal study design, we propose to measure serial leukocyte telomere length (LTL) from already existing stored (n=4204) and newly collected (n=1000) buffy coat samples in 1794 Fels Longitudinal Study participants ranging in age from 18-93 years. Fels Longitudinal Study participants have been repeatedly measured over their entire lifetime for body composition and metabolic markers. Over time, more advanced measures of body composition such as visceral and subcutaneous abdominal adiposity using MRI, and novel blood chemistries such as inflammatory markers have been also been collected. Whole genome single nucleotide polymorphism (SNP) data are available on a large subset of these participants to search for genes influencing telomere biology. This uniquely valuable cohort presents a readily available, cost-effective, and powerful resource for understanding the relationship between telomere biology and cardiometabolic health. The specific aims of the proposed study are: 1) to examine longitudinal associations between adiposity traits, telomere length, and metabolic risk in 1794 adults, 2) to examine cross-sectional relationships between newly collected telomerase activity, telomere length, adiposity traits, and metabolic risk factors in a subset (N=1000) of participants, and 3) to identify genetic variants influencing telomere length and telomerase activity and to use Mendelian Randomization to examine causal associations among obesity, telomere biology and metabolic risk in a subset (N=1247) of study participants. The results of this proposed study will provide important information about how telomere biology is linked to obesity, aging, and cardiometabolic disease risk. Further, this information will aid in the assessment of risk, prevention and treatment of accelerated aging and chronic disease.